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Expert panel discusses concerns, opportunities surrounding biosimilars in the US
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Biosimilars remain an unfamiliar and oftentimes controversial topic among physicians in the U.S. Unanswered questions surrounding both the scientific and legislative issues associated with their introduction have left many physicians in the dark.
To help shed light on the topics at hand, Healio assembled a distinguished panel of experts from five medical specialties to discuss their hopes and concerns for the introduction of biosimilars to the U.S. marketplace.
Level of enthusiasm for biosimilars
Leonard H. Calabrese, DO: I am extremely enthusiastic. This is a new dawn in therapeutics and I am excited only because this has so much in the way of potential for societal benefits. At the level of clinical responses to patients, this does not offer them anything. That is, if they are taking a biosimilar and switch from the originator they will be neither better nor worse for taking it. On the other hand, if we are like Norway we potentially could save up to 50% of the originator’s cost. Humira’s current list price is $53,000 a year, essentially double what it was when it came on the market. The ramifications of this are that if our society has these great savings like what has been potentially calculated, that may mean many more people who are unfortunate and do not have access to biologics may be able to start them. At the level of the patient, it does not necessarily mean that much unless they are going to save money themselves.
Anthony P. Fernandez, MD, PhD: I am very enthusiastic about the introduction of biosimilars in the U.S. The hope is that their introduction will make safe and effective biologic medications more accessible to patients who need them; make it easier for physicians to prescribe them; and result in tremendous health care savings. It is no secret we spend a lot on health care in the U.S., and one of the biggest drivers of cost right now are biologics. Biosimilars are expected to save tens of billions of dollars over the next decade in the U.S.
David T. Rubin, MD, FACG, AGAF, FACP, FASGE: I am cautiously optimistic that the arrival of biosimilars in the United States will improve access and provide additional resources for patients with Crohn's disease and ulcerative colitis. However, I am unconvinced that the competitive market and decreased cost to payers will translate into reduced copays or insurance premiums for our patients. I also remain unconvinced that access to these therapies and the bureaucratic requirements to get them pre-authorized and reauthorized will change.
John Sweetenham, MD, FACP, FRCP: My own personal level of enthusiasm for these agents is high. They present a somewhat lower cost alternative and, really, that cannot be bad. What we’re going to learn is that although there may be minor differences in activity between these agents and the innovator compounds, the fact is that individual batches of innovator compounds are not identical, so I’m not really anticipating that there will be any huge difference in activity between the biosimilars and the original compounds. The only thing curbs my enthusiasm a little bit is that the uptake is going to be very slow until physicians and prescribers have a better understanding of what these agents are, and of the regulatory process that gets them licensed. They will need to understand that it is not going to be the same process, and they are not going to see big randomized trials of these biosimilar agents against the innovator compound for every indication; that simply is not going to happen.
Alan J. Garber, MD, PhD: My level of enthusiasm is not very high, particularly in the area of biosimilar insulin products. The whole idea behind biosimilars was to lower the cost of drugs, as biologics have been some of our priciest medications and costs of these drugs have been escalating rather dramatically in recent years. Insulins are a unique protein molecule in which minor changes in structure or in the nature of the excipients in the solution have major changes on the pharmacokinetics and idiosyncratic patient responses to the preparation. Patients are extraordinarily sensitive to the hypoglycemic potential of insulins and these changes can be seen almost immediately if the nature of preparations being administered is changed. The chief concern will be the transfer of well-controlled patients from insulin A to insulin B — whether from reference product to biosimilar, or from biosimilar to biosimilar — by dispensing agents without prior approval from physicians. That puts the patient at risk and makes the physician unaware of the problem.
In large measure, the issue of cost control is far more complicated than it seems at first glance. Although the manufacturers catch blame for escalating costs, it appears the pharmacy benefit managers (PBMs) are reaping most of the benefit of the price increases, and that is because insurance companies have been the designated arbiter of health care costs — essentially by government action. This empowers PBMs to negotiate prices. The treatment decision-making process has been usurped by PBMs; patients and physicians are just grist for the mill here and we are losing sight of what is best for our patients to produce what is cheapest and most profitable. All of which is antithetical to the concept of personalized health care delivery. According to Congress we need biosimilars to drive down the cost of medications, and I understand that they have gotten expensive, but the right to substitute or force different drugs on people — patients and physicians, alike — is not necessarily going to optimize health care, just profits.
Reservations surrounding biosimilar implementation
Fernandez: There will always be questions about how a biosimilar will compare with the reference product in terms of efficacy and safety when it is first introduced into practice. Although a biosimilar must have the same amino acid sequence as the reference biologic, this does not mean the two will be identical. Many factors, including three-dimensional folding, presence of impurities, and post-translational modifications may differ between a biosimilar and its reference biologic and affect the activity of a biosimilar. Any difference at all could adversely affect the efficacy and/or safety of the biosimilar. There are historical examples where small manufacturing differences of biosimilars resulted in differing efficacy, safety and immunogenicity profiles.
Also, since this group of medications is relatively new, regulatory steps leading to approval may change with time as biosimilars are introduced and we learn more about how to ensure adequate similarity with reference biologics. That said, biosimilars for Infliximab (Remsima and Inflectra) are already available in more than 70 countries and so far, post-marketing exposure studies have found good clinical outcomes, safety, efficacy, and no increased immunogenicity.
In fact, the European Union has almost a decade’s worth of experience with biosimilars. They have had over 20 biosimilars approved across 6 classes. Only two were subsequently withdrawn. Importantly, there have been no concerning efficacy or safety concerns with these biosimilars and they have resulted in significant decreases in cost. So hopefully similar experiences without significant setbacks occur in the United States.
Sweetenham: Their advent has changed the paradigm. I have two reservations: One, I do not believe the industry has done a very good job in terms of bringing these agents to market and providing information and education on what they are, how they work and how they are developed. There has been a deficiency there that, to a large extent, is the responsibility of the companies producing these drugs and they have not done a tremendous job explaining them.
Second, at a more philosophical level, it does concern me that a number of companies are investing very large sums of money to produce new agents which essentially are identical in terms of their activity to existing agents. On one level, you can argue that it is investment in cancer that is not aimed at improving the outcome, it is just aimed at producing a cheaper product. But then in the bigger picture, the argument would be that from a societal perspective that is a good thing because it will hopefully give access to these very active drugs to more people.
Garber: It is one thing to have biosimilars that are not interchangeable. If you prescribe a biosimilar with a product unique identity so you can attribute adverse effects, then you should stay with that product. Switching produces problems, or at least has potential to produce problems. And if you are not aware of switching, as the prescribing doctor you are certainly going to be aware of it when there is an adverse reaction and you do not know the cause. This is basically uncompensated effort on the part of the physician, and everybody just expects us to accept it and move on; it is all part of caring for patients. It takes away from seeing the patient, it takes away from considering the patients’ needs and it is unproductive effort.
Rubin: There are the theoretical concerns about potential immunogenicity related to indiscriminate changes of therapies from biosimilars to originators and vice versa, but there is the very real concern about the logistical challenge of making switches seamless, so that patients do not suffer delays in their therapy and result in loss of response and reactivation of their condition. We see too often that when insurance makes changes or when there is confusion about the authorization or switching process for any therapies, there is back and forth paperwork confusion and lack of appropriate communication and availability by payers, which results in the patient suffering. I have repeatedly stated that any plan to switch patients from their current therapy to a biosimilar must be seamless. This sounds easier than it actually will be, and I am quite concerned. I also remain concerned about full disclosure regarding why patients need to be switched. Insurance companies should be mandated to disclose reasons for switching, as well as full transparency regarding their denials and reasons for denials. Right now, such denials are communicated under the veil of "policy," but we know the policies are very often driven by financial reasons rather than medical ones. A good example is the patient who is losing response to one anti-TNF drug and drug levels suggest there is plenty of drug present. Medical management in this scenario dictates that a different mechanism of disease control is required. Yet, too often insurance companies require that the patient receive another drug in the same class. This makes no medical sense, but I firmly believe it is driven by the cost of the therapies rather than anyone paying attention to how to manage these patients better. It is both unethical and medically dangerous to expose people to management based on these principles. My concern is that when biosimilars arrive, there will be even more confusion regarding how to treat our patients best.
Calabrese: There is a dialogue on biosimilars that deals with technical questions that surround these drugs — are they truly equivalent in terms of efficacy, safety, pharmacokinetics and immunogenicity? And thus far, to my eye, all the trials that I have seen have suggested that they are. The second reservation that people have is extrapolation. That means that the burden of proof to these companies producing biosimilars is much less than the originators. That does not sit well with everyone, but thus far I have no reason to doubt their equivalence. The last issue, which is a technical sticking point for biosimilars, is interchangeabilty. That is, who has the license or the right to interject a biosimilar into the patient’s care. Is it the treating physician who says it is time to try this biosimilar? The other inflection point that people are very concerned about is that the insurance company or dispensing pharmacies will independently take the right to substitute a biosimilar for the originator and make this a decision that the doctor and patient do not have to agree to. We do not have any data on switching between biosimilars and the originator products, and to address that there are multiple pieces of legislation in multiple states that would govern this type of interchangeability. To me, it is something that just needs to be worked out. Though four are approved, we do not have any biosimilars in rheumatology right now that are in use, but once we get out into that space all these things will clarify themselves. There are a lot of people taking a lot of caution and concern about the interchangeability issue, and hopefully it will be worked out to everyone’s satisfaction.
Foreseen obstacles
Rubin: It is essential that biosimilars have unique naming designations, and that, per FDA requirements, appropriate post marketing surveillance studies be performed to fully describe the impact of switching or interchanging therapies. Full interchangeability requires studies of switching between therapies, and back and forth. That type of study has not been performed in inflammatory bowel disease and, to my knowledge, in other disease states, either. My additional concern is that once the drugs are available on the market, there will be no incentive for companies to invest in the disease states or to help us understand better how to manage our patients and to use these appropriately. Although, current companies that are bringing biosimilars to the U.S. market have engaged in a dialogue to suggest they have an interest in our communities … We will see.
Sweetenham: Acceptance is an obstacle. In fairness to the FDA, they are taking a reasonable approach. I do not see any major regulatory obstacles. Physician acceptance is an obstacle — many do not know what biosimilars are. When they do, they look for clinical evidence. In lymphoma, there is a biosimilar rituximab. Some believe they need trials in all areas for innovators, which is wrong. Interchangeability is not an obstacle except when considering who will make the decision on which biosimilar we use. As we see more health care consolidation, health care systems will make decisions on which we use. That is a big factor, though I am most concerned about the education gap among physicians.
On the pathway to licensing for these drugs, they have recognized that if you can prove in one clinical setting that these drugs have equivalence to the innovator in terms of their clinical activity, then it is going to be reasonable to extrapolate that evidence into other indications. That is, in my opinion, a very sensible approach. I know a lot of purists I have spoken to in the lymphoma world have said ‘no, these have to be compared head-to-head in big randomized trials against the innovator compound for every indication and every clinical situation.’ That is, number one, not realistic; number two, is simply financially not sustainable because it would simply push the cost of those drugs right back up again; and number three, not necessary because if we accept that it is the exact same or close to the exact same molecule and it has similar activity in one or two clinical indications, that should be enough.
Calabrese: The obstacles and considerations are that these issues [of interchangeability] will be taken out of the hands of the doctors and patients and, at least at this juncture, I hope that does not occur.
Fernandez: One obstacle is as simple as how do we appropriately name biosimilars? In terms of biosimilars that will affect dermatology, there are already as many as 12 biosimilars for adalimumab in development, nine for etanercept, five for infliximab, and nine for rituximab. So, appropriate naming of products is critical to distinguish each biosimilar from one another and from their reference product. A standardized system of naming that ensures this is needed.
Additionally, the pre-clinical and clinical criteria for regulatory approval will likely be highly scrutinized and debated as biosimilars are introduced. For example, the FDA has issued guidelines concerning how companies should appropriately determine preclinical biosimilarity, but critics have argued these guidelines are too vague and different companies may be doing different tests. Although, criticism and scrutiny is not necessarily a bad thing, and standardization of preclinical analytic testing is important,
I can imagine that over time approval criteria may change and this could result in delayed approval of some biosimilars if companies are unprepared for changes that occur mid-development of a product.
Finally, interchangeability will eventually need to be addressed. It is currently thought frequent switching of biosimilars will increase immunogenicity and presence of anti-drug antibodies since even subtle differences in impurities or post-translational modifications can trigger an immune response to biosimilar agents. So, the current thought is that frequent switching between the reference product and multiple biosimilar agents should be avoided by physicians or pharmacists. Time will tell if this holds true.
Garber: So far in the insulin arena, we have good manufacturers making these biosimilars – Lily is making their follow-on, Basaglar, and Merck has a follow-on insulin. But, suppose you have drug company X in some distant land somewhere, the FDA must go out and inspect the plant to be able to approve its sale in the U.S., but continuing supervision is less now on generic manufacturers than on the originator or reference compound manufacturer. And if the same is true on protein molecules, you have the potential for far more to go wrong.
How clinicians can prepare for biosimilar introduction
Calabrese: Clinicians will need to understand the principles of biosimilars; they must understand that these are basically equivalent drugs that have similar plusses and minuses, particularly immunogenicity. If you are on originator A and you develop antibodies to it, you are not going to give biosimilar A because they will cross react. That is a basic principle, and people will appreciate that in time. Biosimilars are not biobetters; there is no advantage to switching to a biosimilar in terms of increased efficacy or enhanced toxicity, for the most part, so be appreciative of that. The nomenclature of these biosimilars is important and right now there is some debate over how they will be named, so we need to keep our eye on that. Lastly is the cost factor. I am a cynic — in the U.S. we are the world’s best at making the most expensive drugs. If Finland saves 50%, I am fearful that we are going to save far less than that, so we should try to wring every dollar out of this that we can as a society. I view this as a matter of social justice, and I am all-in.
Rubin: It is essential that our colleagues seek out appropriate information and education from credible sources. The American College of Gastroenterology featured information about biosimilars at their meeting in October in Las Vegas, and our other societies, including the Crohn's and Colitis Foundation, have provided some educational material for patients and providers. The Foundation also has a position statement online that discusses the issues and position of the organization.
Sweetenham: The primary issue is the education gap. Clinicians should learn about biosimilars, about the rationale behind their development, how they are produced, and gain insight into interchangeability and extrapolation. There is a lot of good literature out there now that explains these issues. We extrapolate all the time. In fairness, it is not always the case, but the simple fact is, it is just a part of what we do.
Fernandez: It is important for all physicians who may prescribe biosimilars to become thoroughly familiar with the potential benefits and concerns associated with these medications. It is also important to be familiar with the approval processes that are in place for biosimilars.
Furthermore, it is important for us to have centralized databases and registries in place so we can monitor patients on biosimilars closely to better assess safety and efficacy compared to reference products. Detecting small changes in safety and efficacy can be quite important and will require collecting data prospectively with lots of patients.
What is your 20-second take-home message?
Fernandez: There is no disputing that biosimilars are coming, so educate yourself now. This will help ensure you are prepared to educate your patients about biosimilars, address any problems that arise once they are available, and continue optimizing the care you provide.
Garber: You get what you pay for. There is no doubt that biologics have gotten expensive, but biologics have become major consumers of health care dollars because they are effective. This has the potential to threaten the effectiveness and increase the adverse events surrounding these molecules as medications.
Rubin: Biosimilars are coming to the United States, but we must be vigilant regarding their appropriate use and not let cost savings to payers dictate how we manage our patients. We also must be very careful about indiscriminate switching without seamless communication and ongoing disease management.
Sweetenham: Biosimilars are certainly going to get much more widespread use. As providers, we must accept that as health care consolidation continues and as value in health care continues, it is quite likely that the decisions about which of these biosimilars are used will be made at a system level and not at an individual provider level. As prescribing physicians who are taking care of these patients, we need to understand how they are produced, we need to understand the rationale for their use and we need to get familiar with them because as the purchasing power of big health care systems increases and value becomes a bigger emphasis for us all, we may not be the primary decision makers in terms of which of these drugs we give to our patients.
Calabrese: Biosimilars are here and they are knocking at the door for our use, we merely need to be able to recognize these agents for what they are and understand the principles of interchangeability and extrapolation to use them. The last thing is that I hope these decisions will largely remain in the hands of the doctors and patients, but I am fearful that they will not.
For more information:
Leonard H. Calabrese, DO, is chief medical editor of Healio Rheumatology; and vice chair of rheumatic and immunologic disease at Cleveland Clinic. He can be reached at: calabrl@ccf.org.
Anthony P. Fernandez, MD, PhD, is director of medical dermatology, departments of dermatology and pathology at Cleveland Clinic. He can be reached at: fernana6@ccf.org.
Alan J. Garber, MD, PhD, is chief medical editor of Endocrine Today; professor, departments of medicine, biochemistry and molecular biology, and cellular & molecular biology, Baylor College of Medicine. He can be reached at: agarber@bcm.edu.
David T. Rubin, MD, FACG, AGAF, FACP, FASGE, is a Healio Gastroenterology peer perspective board member; Joseph B. Kirsner Professor of Medicine; section chief, gastroenterology, hepatology and nutrition; and co-director, Digestive Diseases Center at The University of Chicago. He can be reached at: drubin@medicine.bsd.uchicago.edu.
John Sweetenham, MD, FACP, FRCP, is chief medical editor of HemOnc Today; executive medical director and senior director of clinical affairs at Huntsman Cancer Institute, University of Utah. He can be reached at: john.sweetenham@hci.utah.edu.
Disclosures:
Calabrese reports he is a consultant for AbbVie, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Pfizer and Sanofi; and is on the speakers bureau for AbbVie, Bristol-Myers Squibb, Crescendo Bioscience and Genentech. Fernandez reports receiving honoraria from AbbVie, Celgene and Novartis; and research for Mallinkrodt and Roche. Garber reports he is on advisory boards for Novo Nordisk and Merck. Rubin reports consulting for and has received grant support from AbbVie, Amgen, Janssen, Pfizer, Samsung/Bioepis and Takeda; and is chair, Government and Industry Affairs Committee, Crohn’s & Colitis Foundation of America. Sweetenham reports no relevant financial disclosures.